Iberdomide Approval Elevates MRD’s Role in Myeloma: Prerna Mewawalla, MD

On August 13, the FDA approved the triplet of iberdomide (Zenbexus; Bristol Myers Squibb) plus daratumumab/hyaluronidase-fihj and dexamethasone (IberDd) for relapsed/refractory multiple myeloma (RRMM). In this latest episode of Director’s Cut with Prerna Mewawalla, MD, director of stem cell transplant and cellular therapy at Allegheny Health Network and associate professor of medicine at Drexel University College of Medicine, she discussed this FDA approval. The conversation touched on how the triplet fits into an increasingly crowded treatment landscape, what the approval signals about the FDA’s growing acceptance of minimal residual disease (MRD) status as an end point, how iberdomide’s mechanism sets it apart from older immunomodulatory drugs (IMiDs), and what simultaneous international review through Project Orbis could mean for global access.

A New Option in a Crowded Field

Mewawalla noted that the relapsed/refractory myeloma space is already dense with options, including bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapy, and antibody-drug conjugates. Even so, she said a new treatment is welcome, particularly because iberdomide combined with daratumumab and dexamethasone has shown activity in patients who have already failed IMiDs such as lenalidomide and pomalidomide.

She pointed out that access to CAR T-cell therapy or bispecifics is not universal and varies by geography and institutional capability, making an option like IberDd valuable for patients who cannot readily reach those more resource-intensive therapies. She also highlighted a distinct immunologic advantage: iberdomide does not appear to impair T-cell fitness and may actually enhance it. Because of that, she raised the possibility of using iberdomide as a bridging therapy ahead of CAR T-cell treatment once the drug is more broadly incorporated into practice.

With IMiDs, generally what we see is because they bind with lesser affinity, they actually cause more of a cell arrest compared to CELMoDs, which actually cause cell death because of the affinity to binding the cereblon pathway.

What MRD-Based Approval Signals for Myeloma Drug Development

The approval was supported by MRD negativity data from the EXCALIBER-RRMM trial (NCT04975997), rather than mature progression-free survival (PFS) or overall (OS) survival data. Mewawalla described this as evidence of a genuine regulatory shift. She traced it back to 2024, when the FDA’s Oncologic Drugs Advisory Committee voted to accept MRD at defined time points as an end point in myeloma trials.

In her view, this shift allows effective treatments to reach patients faster, since PFS and OS outcomes in myeloma can take years to mature. She noted that MRD status assessed between 9 and 12 months can now support approval decisions, and she called this trial the first the FDA has approved on the basis of MRD data alone. She expects it to be the first of many, with MRD-based approval ultimately shortening the time between a drug demonstrating efficacy and patients being able to access it.

How Does Iberdomide’s Mechanism Differ From Older IMiDs?

Mewawalla explained that cereblon E3 ligase modulators (CELMoDs)—a class that includes iberdomide and mezigdomide—work, like IMiDs, by binding to cereblon. The key difference is affinity: CELMoDs bind cereblon more tightly, driving degradation of the transcription factors ikaros and aiolos and resulting in cell death. IMiDs, which bind with lower affinity, tend to produce cell cycle arrest rather than cell death.

She also outlined 2 additional distinctions. First, CELMoDs were engineered to be stronger immune activators, producing more robust T-cell and natural killer cell activation, which makes them attractive combination partners for immunotherapy. Second, their nonhematologic toxicity profile is generally more favorable than that seen with IMiDs. Taken together, she suggested these mechanistic and tolerability differences support continued interest in the broader CELMoD class for myeloma.

What Project Orbis Could Mean for Global Rollout

Mewawalla described a longstanding frustration in oncology: even when global trial data are compelling, patients in different countries often wait vastly different lengths of time for access to the same drug. Project Orbis addresses this by allowing the FDA and participating international regulatory agencies to review oncology applications concurrently.

She was careful to note that concurrent review does not guarantee simultaneous approval. What Project Orbis does accomplish, in her view, is narrowing the regulatory lag between countries. She framed this as particularly important for a disease like myeloma, where treatment approaches are increasingly global and clinical trials routinely enroll patients across multiple countries.